Analysis of arsenic in inducing ROS, signaling pathways, and lung carcinogenesis

描述（由申请人提供）：砷广泛分布在环境中，如土壤、矿物质、烟雾、受污染的空气和水。流行病学研究表明，无机砷暴露诱发肺癌、皮肤癌、肝癌和膀胱癌。然而，砷致癌的病因学和分子机制仍有待阐明。砷还与非恶性肺血管疾病密切相关。我们的初步结果表明，暴露于砷的肺上皮细胞产生高水平的活性氧（ROS）。砷诱导AKT和ERK 1/2激活，并增加HIF-1表达和VEGF转录激活。我们假设砷通过ROS信号传导诱导致癌，ROS信号传导反过来调节PI 3 K、AKT、ERK 1/2和HIF-1。为了验证这个假设，我们将执行以下两个目标。目的1：研究砷对肺上皮细胞内ROS的诱导作用及其机制，探讨砷是否通过ROS的产生来调节PI 3 K、AKT和ERK的激活。目的2：探讨砷在肿瘤发生中的作用，以及砷是否通过ROS的产生、PI 3 K、AKT、ERK 1/2和HIF-1的表达诱导肿瘤发生。我们将研究砷诱导肿瘤生长的信号通路和调节其进展的分子。了解砷的致癌作用及其机制后，我们将能够在未来开发基于机制的干预措施来预防砷致癌。砷在环境中广泛传播，如土壤，矿物质，烟雾，污染的空气和水。砷是已知的致癌物质，可诱发人类癌症。然而，砷致癌的病因学和分子机制仍有待阐明。在本研究中，我们计划研究砷在诱导与致癌和肿瘤发生相关的信号通路和分子中的作用和机制，并分析这些信号分子在砷诱导肿瘤发生中的作用。这些信息将有助于我们在未来开发基于机制的干预措施，以防止砷诱导的致癌作用。

DESCRIPTION (provided by applicant): Arsenic is widely spread in the environment such as soil, minerals, smoke, contaminated air and water. Epidemiologic studies showed that inorganic arsenic exposure induced lung, skin, liver, and bladder cancers. However, the etiology and molecular mechanisms of arsenic in inducing carcinogenesis still remain to be elucidated. Arsenic is also strongly linked to non-malignant lung vascular diseases. Our preliminary results showed that exposure of lung epithelial cells to arsenic produced high levels of reactive oxygen species (ROS). Arsenic induced AKT and ERK1/2 activation, and increased HIF-1 expression and VEGF transcriptional activation. We hypothesize that arsenic induces carcinogenesis through ROS signaling, which in turn regulates PI3K, AKT, ERK1/2, and HIF-1. To test this hypothesis, we will perform the following two aims. In Aim 1, we will identify which species of ROS induced by arsenic and the mechanism of ROS generation in the lung epithelial cells, then determine whether arsenic regulates PI3K, AKT, and ERK activation through ROS generation in the cells. Aim 2 will determine the role of arsenic in inducing tumorigenesis, and whether arsenic induces tumorigenesis through ROS production, PI3K, AKT, ERK1/2, and HIF-1 expression. We will study signaling pathways and molecules that regulate the progression of arsenic-inducing tumor growth. After we learn the effects and the underlying mechanism of arsenic in inducing carcinogenesis, we will be able to develop mechanism-based interventions to prevent carcinogenesis induced by arsenic in the future. PUBLIC HEALTH RELEVANCE: Arsenic is widely spread in the environment such as soil, minerals, smoke, contaminated air and water. Arsenic is known carcinogen for inducing human cancer. However, the etiology and molecular mechanisms of arsenic in inducing carcinogenesis still remain to be elucidated. In this study, we plan to study the roles and mechanism of arsenic in inducing signaling pathways and molecules that are associated with carcinogenesis and tumorigenesis, and to analyze these signaling molecules in arsenic-inducing tumorigenesis. This information will be useful for us to develop mechanism-based interventions to prevent arsenic-inducing carcinogenesis in the future.